Tumor Small Extracellular Vesicle‐Transmitted LncRNA CATED Promotes Platinum‐Resistance in High‐Grade Serous Ovarian Cancer

Abstract High‐grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum‐resistance is a serious challenge in its treatment. Long non‐coding RNAs (lncRNAs) play critical regulatory roles in the occurrence and development of cancers. Here, using RNA sequencing of tumor small extracellular vesicles (sEVs) from HGSOC patients, the lncRNA CATED is identified as significantly upregulated in both tumors and tumor‐derived sEVs in platinum‐resistant HGSOC, and low CATED levels correlate with good prognosis. Functionally, CATED enhances cisplatin resistance by promoting cell proliferation and inhibiting apoptosis in vitro and in vivo. These effects could be transferred via CATED‐overexpressing sEVs from donor cells and HGSOC tumor sEVs. Mechanistically, CATED binds to and upregulates DHX36 via PIAS1‐mediated SUMOylation at the K105 site, and elevated DHX36 levels increase downstream RAP1A protein levels by enhancing RAP1A mRNA translation, consequently activating the MAPK pathway to promote platinum‐resistance in HGSOC. Antisense oligonucleotide mediated knockdown of CATED reverse platinum‐resistance in sEV‐transmitted mouse models via the DHX36‐RAP1A‐MAPK pathway. This study newly identifies a sEV‐transmitted lncRNA CATED in driving HGSOC platinum‐resistance and elucidates the mechanism it regulates the interacting protein through SUMOylation. These findings also provide a novel strategy for improving chemotherapy in HGSOC by targeting CATED.